title: Cumulative mechanisms of lymphoid tissue  fibrosis and T cell depletion in HIV-1  and SIV infections.
abstract: The hallmark of HIV-1 and SIV infections is CD4(+) T cell depletion. Both direct cell killing and indirect mechanisms related to immune activation have been suggested to cause the depletion of T cells. We have now identified a mechanism by which immune activation-induced fibrosis of lymphoid tissues leads to depletion of naive T cells in HIV-1 infected patients and SIV-infected rhesus macaques. The T regulatory cell response to immune activation increased procollagen production and subsequent deposition as fibrils via the TGF-β1 signaling pathway and chitinase 3-like-1 activity in fibroblasts in lymphoid tissues from patients infected with HIV-1. Collagen deposition restricted T cell access to the survival factor IL-7 on the fibroblastic reticular cell (FRC) network, resulting in apoptosis and depletion of T cells, which, in turn, removed a major source of lymphotoxin-β, a survival factor for FRCs during SIV infection in rhesus macaques. The resulting loss of FRCs and the loss of IL-7 produced by FRCs may thus perpetuate a vicious cycle of depletion of T cells and the FRC network. Because this process is cumulative, early treatment and antifibrotic therapies may offer approaches to moderate T cell depletion and improve immune reconstitution during HIV-1 infection.
authors.affiliation: Department of Microbiology, Medical School, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Zeng
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Smith
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Wietgrefe
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Southern
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Schacker
authors.forename: Cavan S
authors.initials: CS
authors.lastname: Reilly
authors.forename: Jacob D
authors.initials: JD
authors.lastname: Estes
authors.forename: Gregory F
authors.initials: GF
authors.lastname: Burton
authors.forename: Guido
authors.initials: G
authors.lastname: Silvestri
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Lifson
authors.forename: John V
authors.initials: JV
authors.lastname: Carlis
authors.forename: Ashley T
authors.initials: AT
authors.lastname: Haase
mesh_terms: D054392:Adipokines; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D000071451:Chitinase-3-Like Protein 1; D005347:Fibroblasts / Q000166:cytology; D006023:Glycoproteins / Q000378:metabolism; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D015851:Interleukin-7 / Q000378:metabolism; D037102:Lectins / Q000378:metabolism; D008214:Lymphocytes / Q000166:cytology; D008253:Macaca mulatta; D012192:Retroviridae Infections / Q000276:immunology*; D015398:Signal Transduction; D015302:Simian Immunodeficiency Virus / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D054392:Adipokines; C084533:CHI3L1 protein, human; D000071451:Chitinase-3-Like Protein 1; D006023:Glycoproteins; D015851:Interleukin-7; D037102:Lectins; D053773:Transforming Growth Factor beta1